MILITARY M EDICINE, 179, 11:112, 2014

The Potential for DHA to Mitigate Mild Traumatic Brain Injury Julian E. Bailes, MD; Vimal Patel, PhD

ABSTRACT Scientific knowledge of omega-3 fatty acids (FAs) has grown in the last decade to a greater understand­ ing of their mechanisms of action and their potential therapeutic effects. Omega-3 FAs have shown therapeutic potential with respect to hyperlipidemia, depression, attention-deficit hyperactivity disorder, and mild cognitive impairment. Laboratory evidence and clinical interest have grown such that omega-3 FAs have now assumed a role in concussion management. This has coincided with recent research that has also helped to increase the scientific understanding of cerebral concussion; although concussion or mild traumatic brain injury was assumed to be a malfunctioning brain without anatomical damage, we now know that there is the potential for damage and dysfunction at the cellular and microstructural levels. Specifically, with concussion abnormal metabolism of glucose may occur and intracellular mitochondrial dysfunction can persist for several days. In this article, we discuss the role of omega-3 FAs, particularly docosahexaenoic acid, in concussion management.

INTRODUCTION The Sport Group described concussion as “a complex patho­ physiological process affecting the brain induced by traumatic biomechanical forces.”1 The Centers for Disease Control and Prevention recently provided a collective and comprehensive definition for concussion and mild traumatic brain injury (MTBI),2 using the two terms interchangeably: “A mild traumatic brain injury (MTBI) or concussion is defined as a complex pathophysiologic process affecting the brain, induced by traumatic biomechanical forces secondary to direct or indirect forces to the head. MTBI is caused by a jolt to the head or body that disrupts the function of the brain. This disturbance of brain function is typically associated with normal structural neuro­ imaging findings (i.e., CT scan, MRI). MTBI results in a constellation of physical, cognitive, emotional, and/or sleep-related symptoms that may or may not involve a loss of consciousness (LOC). Duration of symptoms is highly variable and may last from several minutes to days, weeks, months, or longer in some cases.” Concussion occurs in what has been characterized as a “metabolic mismatch” during which relative cerebral blood flow may decreases while glucose demand increases. This situation is the result of uncontrolled release of excitatory neurotransmitters during biomechanical injury which bind to iV-methyl-D-aspartate, leading to neuronal depolarization in which there is an influx of calcium and an efflux of potassium ions. The subsequent increase in excitatory activity caused by the increased extracellular K+ is followed by diffuse neuronal activity depression. To restore the ionic imbalance and because of gene upregulation, there is increased activity of the sodium-potassium pump which requires additional NorthShore Neurological Institute, NorthShore University Health System, University of Chicago Pritzker School of Medicine, 2650 Ridge Avenue, Kellogg 3rd Floor, Evanston, IL 60201. doi: 10.7205/MILMED-D-14-00139

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adenosine triphosphate thereby resulting in increased glu­ cose metabolism.3'4 Following MTBI, while glucose metabolism initially increases a period of hypometabolism follows. This hypometabolic state has been shown to persist for up to 10 days in animal studies and in some cases can last up to 1 month or longer in humans, and has been to be linked to lingering postconcussion symptoms.3'4 In addition, other physiological events associated with MTBI are decreased magnesium levels in the brain and blood, diffuse axonal injury, persistent calcium accumulation, and alterations in neurotransmitter activity.5 Research has found that in some instances of MTBI both cellular and ultrastructural damage may occur. Such injury has been documented to occur in the microtubules and neurofilaments, which are responsible for the normal move­ ment of nutrients from the neuronal soma into the axonal and dendritic connections. This axoplasmic flow is interrupted from mechanoporation within the projecting fibers, which may lead to the accumulation of tau protein within axonal retraction bulbs. Normally, tau protein, a leading neuronal structural protein, is maintained in a nonhyperphosphorylated state by two protein phosphatases. If there is a disturbance in the balance of phosphatases and kinases that regulate tau, hyperphosphorylated tau becomes ubiquitinated, which can lead to the formation of neurofibrillary tangles. Autopsy stud­ ies of the brains of both contact sports athletes and military veterans have documented this tauopathy, neurofibrillary tangles, and the syndrome of chronic traumatic encepha­ lopathy.6 Recent experiments with radioactive tracers have shown that the axonal injury may occur in a nonlethal concussive model and that progressive axonal swelling and distur­ bance in axonal transport results in the hours and days following the injury. Omega-3 FAs are long-chain polyunsaturated fatty acids (PUFAs) with many documented health benefits, most notably in cardiovascular disease.7 In mammalian systems, including humans, the two primary omega-3 FAs are ecosapentaneoic acid (EPA) and docosahexaenoic acid (DHA), traditionally

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Role of Omega-3 FAs in Mitigating MTB1

isolated from oils separated from fatty fish or a nonmarine, microalgae source. The advantage of the latter is the lack of exposure to potential marine environment contaminants, such as mercury, dioxin, and polycarbon benzenes. EPA and DHA can be obtained as nonprescription supplements classified by the U.S. Food and Drug Administration under Generally Recognized as Safe guidelines. In addition to the known car­ diovascular and anti-inflammatory effects, emerging evidence suggests potential benefit from the use of omega-3 FA supple­ ments in improving neurological outcomes from both trau­ matic and ischemic mechanisms.8-11 Although the beneficial effects of omega-3 FAs for cardio­ vascular, anti-inflammatory, developmental, and general health have been reported during the past decade, the advan­ tages for the athletic and military populations, both of which have exposure for multiple or repetitive MTBI, now are being realized. These effects are summarized below. DISCUSSION Mechanisms of Structure and Action of DHA DHA is one of the human brain’s primary FAs, constituting high concentrations in the phospholipids of neuronal plasma membranes and synaptic vesicles. Human brain omega-3 FA content consists of 97% DHA, whereas the retina consists of 93%.12 One might predict that membranes rich in DHA would be exceptionally thick since it is a very long-chain FAs with 22 carbons. However, despite its length it is highly flexible, such that its actual three-dimensional structure is of a pyramid. This makes cell membranes containing DHA phospholipids very thin, subsequently more permeable and to have looser lipid packing than membranes composed of other FA-containing phospholipids.13 Furthermore, these membranes create an appropriate environment for integral proteins such as receptors, ion channels, enzymes, and peripheral proteins that are highly condensed in neurons. In addition to constituting a major structural function, DHA also has anti-inflammatory properties, and a portion is retroconverted to EPA within mammals, including humans.14 EPA is a precursor of the PG3 series of prostaglandins and resolvins, which have anti-inflammatory effects. DHA also stimulates neurite outgrowth triggered by nerve growth factor.14'15 The DHA content of the human brain exponentially rises during fetal development and the first few years of life. How­ ever, when dietary deficiency of DHA occurs, the brain retains DHA longer while other organs are depleted. Brain trauma (mild or severe) can cause both acute and long-lasting perturbations in brain phospholipid metabolism, and degra­ dation of neuronal and astrocytic membrane phospholipids has been shown.14-17 This pathological course constitutes an evolving aspect of the secondary injury phase, which may persist for days or weeks.18 Beyond their structural role, PUFAs also serve many important functions such as being involved in intercellular and intracellular signaling.1219 Spe­ cific PUFAs also appear to be neuroprotective at the cellular

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level by providing protection against apoptotic death and through modulation of gene expression.20 Central Nervous System Effects Omega-3 FA intake by fish consumption has been shown to promote brain development and cognitive ability in male adolescents in verbal and visuospatial performance, as well as combined intelligence.21 This association was consistent across both low and highly educated groups.22 There is growing evidence that omega-3 FAs may be beneficial to maintain proper and optimal neural cell mem­ brane structure and function, with resultant improved cogni­ tive function and prevention of dementia.23-31 These studies have shown decreased mental latency, reduction in errors, and improved learning.32 Greater dietary intake of omega-3 FAs in individuals who are omega-3 FA deficient has led to increased phospholipids DHA content, decreased p-amyloid plaque, and reduced neuronal cell apoptosis.33 Progression to dementia, or the conversion of mild cognitive impairment (MCI) to Alzheimer’s disease (AD) and other neurodegenerative diseases including Parkinson’s disease, chronic trau­ matic encephalopathy, and amyotrophic lateral sclerosis, is another major issue affecting those who have been exposed to multiple episodes of cerebral concussion. These long-term consequences of concussion are of concern for the develop­ ment of MCI.34 Indeed, our previous research, involving retired National Football League players, showed that there is a five-fold increased risk of developing MCI in those with a history of three or more concussions during their National Football League playing career.35 Although the research in this area is complex and still developing, Morris et al34 found that adults with higher dietary intake of fish oils, in particular DHA, had a 60 to 70% less risk of having AD. There is evidence from the animal literature suggesting that DHA may ameliorate or lessen symptoms of MCI or the conversion to fully developed AD in humans.23 Depression can be mediated and improved by use of omega-3 FAs.36 Alteration of serum cholesterol levels and the proportion of omega-6 to omega-3 FAs have been shown in depression.37'38 Depression is also a common after effect of contact sports, where we have shown a three-fold increase in the incidence of depression and be proportional to the concussion exposure during a football playing career.39 Mild Traumatic Brain Injury There is recent clinical evidence that omega-3 FAs may play a role in recovery or improvement following critical illness or neurological injury. Hard et al40 showed that nutritional status is vital for optimal metabolic support in patients hospi­ talized with major head trauma. Heller et al41 reported that, of all independent variables in patients with major illnesses and managed within the intensive care unit, supplementation with omega-3 FA was most highly associated with reduced mortality, antibiotic use, and length of hospital stay in

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Role of Omega-3 FAs in Mitigating MTBI

patients with various disease states. In the case of the longest known carbon monoxide and methane poisoning, the Sago mine disaster survivor, it appeared that omega-3 FAs contrib­ uted to his neurological recovery following an initial presen­ tation in deep coma.42 Further anecdotal experience from patients, in critical condition following major head trauma, has led us to believe that omega-3 FAs are beneficial for support in neurological and systemic injury recovery, as well . , 43 44 as survival. ’ Major focus on the management of brain injury has been at limiting the secondary or progressive damage. Thus far, a pharmacological intervention to mitigate the evolving cellu­ lar and metabolic perturbations has not been discovered. Sports-related concussion, although classified as “mild trau­ matic brain injury,” has the advantage that the heterogeneity of major head injury, including hemorrhage, major diffuse axonal injury, cerebrospinal fluid circulation disturbance, and brain contusions, ordinarily do not concomitantly occur. The pathophysiological changes involved with concussion appear to be relatively constant, with both mechanical and cellular injury present, leading to “mechanoporation” of the neuronal membrane, with axonal disconnection often being the final common result.18 Our knowledge of the pathophysiology of cerebral con­ cussion has undertaken significant advances in the last decade.45'46 The vulnerability of the brain, particularly to repetitive impacts, has been recognized to be different from other forms of injury, whereby the brain may attempt to heal and then be reinjured. We have also increased our current understanding concerning the mechanics of human collisions and the resultant alterations and responses at the cellular level as well as long-term changes that may accrue to the neuron and its connections 47 It is also understood that the metabolic effects of sports-related concussion may extend longer than the clinical symptoms, as a result most experts caution against premature return to play 46 48 49 Brain metabolic changes have been shown using magnetic resonance imaging spectroscopy in concussed athletes with normal neuropsycho­ logical studies. Important changes have been proposed at the organizational levels, which are meant to increase the long-term safety of contact and collision sports, particularly American football, but also for other sports where the risk of concussion, including repetitive injury, is significant.6'50'51 All sports which have a significant number of head impacts as a regular part of the game, such as American football, or those in which head collisions are common and in many instances unavoidable, such as ice hockey, soccer, basketball, and others, have inherent risk of concussion. Military person­ nel now have a higher than ever risk of exposure to repetitive MTBI through improvised explosive devices, resulting in an unprecedented rate of nonpenetrating head injury than at any time in our military history. The most definitive strategy to avoid short- or long-term detrimental effects on the human brain is through prevention or mitigation of any structural or cellular damage, which may become cumulative.

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Activities that have the potential for repeated head impacts and concussion carry a significant danger of causing long-term effects.6'35'39,50-52 Recent work in our laboratory and others has shown that in addition to the above innovations, dietary supplementation with the omega-3 FAs, and particularly DHA, may provide additional benefit by exerting a protective mech­ anism at the cellular and neuronal levels. Experimentation with three MTBI paradigms have led us to observe beneficial effects of omega-3 FAs on the mitigation or prevention of brain injuiy when used in an accelerationdeceleration model of concussion. Using a combination of DUA and EPA, and more recently DHA alone, we have demonstrated that a reduction in anatomical injury, as mea­ sured through p-amyloid precursor protein (APP) counts, has occurred.53 Importantly, in a rodent model, DHA has also been shown to have a neuroprotective effect when given as a pro­ phylactic dietary supplement before the injury occurs.54 These results, although preliminary, indicate great potential and also the need for further human studies. In general, the neuroprotective effects appear to be most evident when high doses of DHA (40 mg/kg) are used in rodents. DHA supplements of this dose produced signifi­ cantly better results, compared to controls, through assess­ ment of anatomical damage (in the form of APP counts within injured axons), axonal retraction bulbs, immunohistochemical analysis of cellular factors (such as caspase-3 axons and CD86 macrophages), and behavioral memory measures by water maze testing. When measured using stereological analysis, all DHA dosage groups resulted in statistically sig­ nificant improvement in the numbers of injured axons as assessed by APP counts.54 Further investigation is required given these promising studies for a compound which is ubiquitous, affordable, Food and Drug Administration approved, and safe to improve on the outcomes of traumatic brain injury (TBI), which hereto­ fore has not had effective pharmaceutical intervention. Although prior work from our laboratory with the same head injury model has shown that the postinjury administration of fish oil concentrate rich in EPA and DHA, as well as with DHA alone, significantly reduces the number of injured axons, the concept of prophylactic administration, to particu­ larly vulnerable TBI populations, for instance contact sport athletes or military personnel, is intriguing.51 In addition, new evidence in several other models of cen­ tral nervous system (CNS) pathology indicates that omega-3 FAs have therapeutic potential for improvement in the out­ comes of brain injury.8'9’11,14 Several recent reports also highlight the potential for DHA to provide ischemic brain protection. In a brain ischemic paradigm, Cao et al9 demon­ strated that gerbils pretreated with DHA show a preventative effect on hippocampal injury by reduction of lipid oxidative damage through inhibition of prostaglandin synthesis. The deterioration of membrane phospholipids and cumulative stress from reactive oxygen species as seen in TBI reduces levels of brain-derived growth factor, synapsin I, and cAMP

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Role of Omega-3 FAs in Mitigating MTB1

responsive element-binding protein, resulting in synaptic dysfunction and cognitive impairment.10 Wu et al,8'27 using a rodent fluid percussion injury model, showed positive results with pretreatment with both DHA and EPA for 4 weeks including 1 week following the injury. They found positive enzymatic measures, normalized levels of hippocampal brain-derived growth factor, and its down­ stream effectors. There is growing evidence that suggests that endoplasmic reticulum (ER) stress has a role in the pathogenesis of TBI and various neurodegenerative disorders.55,56 ER stress results in excess accumulation of misfolded protein, which triggers the unfolded protein response, a complex signaling network that reduces ER stress and restores homeostasis. However, if the unfolded protein response fails to reestablish the ER to normality, ER stress causes cell dysfunction and death. In a rodent TBI model, DHA has been shown to have a potentially beneficial role in this response by reducing ER stress marker proteins, abnormal protein aggregates, and improve neuronal function model.57 CONCLUSION Promising research now indicates that working through several mechanisms, omega-3 FAs and DHA in particular, may provide advantages for brain health, including as a pro­ phylactic against cerebral concussion. Given the safety pro­ file, purity, availability, and affordability of DHA, it may be considered a beneficial supplement for an athlete, not only for its general health benefits, but also particularly for those at risk or high exposure to repetitive brain impacts. Ongoing and future research in human models should aim to substan­ tiate the preliminary findings of the animal models, which support the use of omega-3 FA supplementation for injury prevention and performance enhancement in the athlete and military personnel. ACKNOWLEDGMENTS The authors appreciate the contributions of Rebecca Kessler for her assis­ tance in the manuscript preparation. Some of the laboratory and clinical experiments described herein have been funded by Martek Biosciences, Inc., for which the author was a consultant.

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MILITARY MEDICINE, Vol. 179, N ovem ber S upplem ent 2014

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The potential for DHA to mitigate mild traumatic brain injury.

Scientific knowledge of omega-3 fatty acids (FAs) has grown in the last decade to a greater understanding of their mechanisms of action and their pote...
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